CN105833283A

CN105833283A - A composition comprising S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl] 2-methylpropanethioate and croscarmellose sodium

Info

Publication number: CN105833283A
Application number: CN201610309140.6A
Authority: CN
Inventors: 米夏埃拉·克拉比赫勒; 贝尔纳德·迈尔; 卡斯滕·温岑伯格
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2010-11-04
Filing date: 2011-10-31
Publication date: 2016-08-10
Also published as: WO2012059447A1; ZA201302954B; IL225780B; NZ609529A; AU2011325235B2; MA34643B1; KR20130083922A; CL2013001164A1; AU2011325235A1; EA025649B1; MX345650B; SG190025A1; MY164729A; EP2635263A1; KR101579659B1; PE20140018A1; AR083693A1; BR112013010704A2; ES2553279T3; ECSP13012603A

Abstract

The present invention relates to a composition comprising: a) S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate, and b) croscarmellose sodium. The present invention also relates to a process for the preparation of a composition comprising the following steps: a) Mixing and granulating, S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate, crospovidone micronized, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl methylcellulose; b) Spraying up to 0.5% by weight of hydroxypropyl methylcellulose in water or in 10% - 30% ethanol by weight/70% - 90% water by weight, onto the granulates obtained according to step a); c) drying the granulates; and d) blending microcrystalline cellulose, colloidal silicon dioxide and sodium stearylfumarate with the dry granulates obtained according to step c).

Description

Comprise 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl Base] amino) phenyl] ester and the compositions of cross-linking sodium carboxymethyl cellulose

The application be PCT international filing date be on October 31st, 2011, PCT international application no is PCT/EP2011/ 069087, China national Application No. 201180053237.0, invention entitled " comprise 2-methyl-prop thio-acid S-[2-([[1- (2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester and the compositions of cross-linking sodium carboxymethyl cellulose " and application point Case application.

The present invention relates to preparation based on hygroscopicity substrate, its preparation method and the purposes in treatment disease thereof.

Display ester, amide or the functional active pharmaceutical ingredient of thioester are generally to moisture-sensitive, and often show Show and the chemical incompatibility of various common drug excipient, therefore can not consider typical compound method, such as base Drug delivery system in lipid.Due to chemistry and physical stability, so drug substance is admixed to hygroscopic polymer Substrate is probably key.When contained active medicine due to there is hydrolytic susceptibility functional group and in water unstable time, Excipient in solid dosage forms may cause sizable stability problem to the absorption of moisture.Although hygroscopicity is gathered in theory Compound can be in conjunction with the moisture in preparation, and thus protection active pharmaceutical ingredient avoids hydrolysis, however it is necessary that the poly-of at a relatively high amount Compound to realize this purpose, this capping (capping) typically resulting in quick-release tablet preparation or cracking.Therefore, generally storing Period must be by suitable preparation and primary package to prevent water adsorption.

There is hydrophobic, the compositions of water unstable compound of waxy denseness, according to this compared to comprising of past The preparation of bright compositions shows more preferable mobility astoundingly.Such as, do not show extremely according to the compositions of the present invention Funnel flow.

In the first aspect, the present invention provide pharmaceutical composition, described pharmaceutical composition comprise have waxy denseness dredge Water, water unstable compound and super-disintegrant.

In second aspect, the present invention provide pharmaceutical composition, described pharmaceutical composition comprise have waxy denseness dredge Water, water unstable compound, super-disintegrant and at least two bulk density diluent less than 800g/L.

The present invention also provides for the method for the cardiovascular disorder for the treatment of or prevention mammal, wherein to the food in one's mouth needing this treatment The pharmaceutical composition provided by the present invention of breast animal administering therapeutic effective dose.

The present invention also provides for the preparation for treating or prevent cardiovascular disorder.For treating or preventing cardiovascular disorder The compositions according to the present invention of purposes is also the part of the present invention.

Preparation based on hygroscopicity substrate may be used for the most stably having the hydrophobic of waxy denseness and hydrolysis sensitivity Property compound, such as cetp inhibitors (CETP inhibitor), and may be used for stably comprising described preparation The physical property of tablet.

Accompanying drawing is sketched:

Fig. 1 is that the 3D of all X-ray sheets of the tablet according to embodiment 1 preparation rebuilds.

Fig. 2 is that the 3D of all X-ray sheets of the tablet according to placebo embodiment A rebuilds.

Fig. 3 shows that 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] ester is brilliant The X-ray powder diffraction pattern of body crystal form (also referred to as A type).

Unless otherwise indicated, the following term used in description and claims has an implication given below:

Term " bulk density " refers to the Density Metric of material loose, uncompacted, and wherein the volume of material includes between granule The air retained.According to European Pharmacopoeia (European Pharmacopeia), graduated cylinder is measured bulk density.

Term " diluent " refers to such excipient, and it fills up the size of tablet or capsule so that it is can actual prepare And facilitate consumer to use.Suitably diluent includes such as acceptable filler, and such as microcrystalline Cellulose is (such as)、 Micronized crospolyvinylpyrrolidone, cellulose powder, the lactose of spray drying, Lactis Anhydrous, a Lactose hydrate, phosphoric acid Hydrogen calcium, sugar, sugar alcohol, corn starch, starch, pregelatinized Starch, colloidal silica, polysaccharide and their mixture.

Term " hydrophobic " refers to water insoluble, it is not easy to absorb moisture, or it is had adverse effect on by water；With water not Perhaps it had extremely low affinity mutually.In other words, dewatering medicament or compound will not spontaneously be dispersed in water.Specifically Ground, hydrophobic refers to logP ＞ 3.Measure logP, or according to the mould developed by Moriguchi in the case of there is no experimental data Type as clogP calculate (S.Moriguchi, S.Hirono, I.Nakagome, H.Hirano, (1994). " Comparison Of reliability of log P values for drugs calculated by several methods (if by The comparison of the reliability of the log P value of the medicine that drying method calculates) " Chem Pharm Bull 1994,42:976-978).

Term " hygroscopic polymer excipient " refers to such polymeric excipient, and it is such as by even as little as The relative humidity of 50%, absorb in room temperature (e.g., from about 25 DEG C) or adsorb and absorb moisture.The moisture absorbed is by such as in room The dynamic moisture adsorption (dynamic vapor sorption) of temperature is measured.Such as, hygroscopicity can according to European Pharmacopoeia- 6th edition (2008), the method disclosed in 5.11 chapters is measured.Dynamically moisture adsorption commercial measurement is by product steam varied about Mass change produced by concentration.Suitably " hygroscopic polymer excipient " have hydroxypropyl methyl cellulose, hydroxy propyl cellulose Substituted hydroxypropyl cellulose plain, low, hydroxyethylmethyl-cellulose, carboxypolymethylene, methylcellulose, ethyl cellulose, hydroxyl second Base cellulose, cellulose acetate, polyvinylpyrrolidone crospolyvinylpyrrolidone, micronized crosslinked polyethylene pyrrolidine Ketone, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, the carboxymethyl cellulose of crosslinking, microcrystalline Cellulose, the microcrystalline cellulose of silication Element, cellulose powder, carboxymethyl starch, starch, pregelatinized Starch or their mixture.Especially, " hygroscopic polymer is composed Shape agent " refer to hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, microcrystalline Cellulose and micronized crosslinked polyethylene pyrrolidine Ketone.Example in room temperature (e.g., from about 25 DEG C) " water-fast hygroscopic polymer " include low substituted hydroxypropyl cellulose, Carboxypolymethylene, ethyl cellulose, cellulose acetate, crospolyvinylpyrrolidone, micronized crospolyvinylpyrrolidone, Carboxymethylcellulose calcium, microcrystalline Cellulose, the microcrystalline Cellulose of silication, cellulose powder and starch.

Term " super-disintegrant " refers to the disintegrating agent the most quickly expanded.In general, super Disintegrating agent is can to obtain the disintegrating agent of same effect so that the partial amount of conventional disintegrating agents uses.The example bag of super-disintegrant Include cross-linking sodium carboxymethyl cellulose (also referred to as cross-linking sodium carboxymethyl cellulose), sodium starch glycollate and crosslinked polyethylene pyrrole Pyrrolidone (also referred to as crospolyvinylpyrrolidone).Cross-linking sodium carboxymethyl cellulose is available commercially from FMC Corp. (trade name) and Avebe Corp. (trade name).Sodium starch glycollate is available commercially from Penwest Pharmaceuticals Co. (trade name) and Avebe Corp. (trade name).Cross-link poly-second Alkene pyrrolidone is available commercially from BASF Corp. (trade nameAnd International Specialty CL) Chemicals Corp. (trade name).Croscarmellose is also available commercially from Mingtai Chemical Co.Ltd (trade name) and J.Rettenmaier&GmbH+Co (JRS) (trade name).Most preferably super-disintegrant is cross-linking sodium carboxymethyl cellulose and crospolyvinylpyrrolidone.

Term " water unstable " refers to there is hydrolytic susceptibility functional group such as ester, amide or thioester.

Term " waxy denseness " refers to that glass transition temperature (Tg) is less than 25 DEG C.

Term " halo " refers to chloro, bromo, iodo or fluoro.

" aryl " refers to monovalent monocyclic or bicyclic aromatic hydrocarbon part.More specifically, term aryl includes but not limited to: benzene Base, 1-naphthyl, 2-naphthyl etc., the most each can be substituted or unsubstituted.

“(C₂-C₆) thiazolinyl " refer to there are 2 to 6 carbon atoms, especially 2 to 4 carbon atoms and there is at least one pair The straight or branched of key.The example of thiazolinyl includes vinyl, acrylic, acrylate-2-thiazolinyl, isopropenyl, n-butene base, isobutene. Base and tertiary cyclobutenyl.

“(C₁-C₈) alkyl " refer to side chain or the straight chain hydrocarbon chain with one to eight carbon atom, such as methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl and heptyl.(C₁-C₆) alkyl is preferred.

" halo-(C₁-C₈) alkyl " and refer to by more than one halogen atom replace, preferably taken by one to three halogen atom The alkyl as defined above in generation.Preferred halo-(C₁-C₈) alkyl is chloro-and fluoro-(C₁-C₈) alkyl.

" aralkyl " refers to formula-R^bc-R^bdPart, wherein R^bdIt is aryl and R^bcIt is (C as herein defined₁-C₆) Alkylidene.

“(C₁-C₆) alkoxyl " refer to formula-OR^abPart, wherein R^abIt is (C as herein defined₁-C₆) moieties. The example of alkoxy portion includes but not limited to: methoxyl group, ethyoxyl, isopropoxy etc..

“(C₃-C₈) cycloalkyl " refer to single saturated carbon ring, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl With ring octyl group.

“C₃-C₈Cycloalkyl C₁-C₈Alkyl " refer to alkyl as defined above, it is by (a C as defined above₃- C₈) cycloalkyl replaced.

" acyl group " refers to formula-C (O)-R^ag、-C(O)-OR^ag’、-C(O)-OC(O)R^agOr-C (O)-NR^agR^ahGroup, its Middle R^agIt is hydrogen, (C₁-C₆) alkyl, halo (C₁-C₆) alkyl or amino, as defined above, and R^ahIt is hydrogen or as defined herein (C₁-C₆) alkyl.

Unless otherwise indicated, all percentage ratios are given with the percentage by weight of the gross weight of compositions.

In specific embodiments, hydrophobic, the water unstable compound with waxy denseness are CETP inhibitor sulfur generations Acid ester derivant, such as those disclosed in EP 1020439 A1.Concrete thioester compound includes having such as formula Those of the compound of I,

Wherein

R is C₁-C₈Alkyl, C₂-C₆Thiazolinyl, halo C₁-C₈Alkyl, C₃-C₈Cycloalkyl, C₃-C₈Cycloalkyl C₁-C₈Alkyl, virtue Base, aralkyl or there are 5 yuan or 6 yuan of heterocyclic groups of 1 to 3 nitrogen, oxygen or sulphur atom,

X¹、X²、X³And X⁴It is hydrogen, halogen, C independently₁-C₈Alkyl, halo C₁-C₈Alkyl, C₁-C₆Alkoxyl, cyano group, nitre Base, acyl group or aryl,

Y is-CO-or-SO₂；And

Z is hydrogen, C₁-C₈Alkyl, C₃-C₈Cycloalkyl or C₃-C₈Cycloalkyl C₁-C₈Alkyl.

In further preferred embodiment of the present invention, CETP inhibitor thioester derivant is thio isobutyrate S-(2- { [1-(2-Ethyl-butyl)-cyclohexane carbo]-amino }-phenyl) ester, it is also referred to as 2-methyl-prop thio-acid S-[2- ([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester, reach plug bent (dalcetrapib) or Formulas I ' chemical combination Thing

2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] ester has been demonstrated Be people (de Grooth etc., Circulation, 105,2159-2165 (2002)) and rabbit (Shinkai etc., J.Med.Chem., 43,3566-3572 (2000)；Kobayashi etc., Atherosclerosis, 162,131-135 (2002)；With Okamoto etc., Nature, 406 (13), 203-207 (2000)) in the inhibitor of CETP activity.2-methyl-prop thio-acid S-[2-([[1-(2-second Base butyl) cyclohexyl] carbonyl] amino) phenyl] and ester have been demonstrated people (de Grooth etc., ibid) and rabbit (Shinkai etc., Ibid；Kobayashi etc., ibid；Okamoto etc., ibid) middle increase plasma HDL cholesterol.Additionally, 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] ester have been demonstrated reduce people (de Grooth etc., with On) and rabbit (Okamoto etc., ibid) in LDL-C.Additionally, 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl fourth Base) cyclohexyl] carbonyl] amino) phenyl] and ester suppression rabbit atherosclerosis progress (Okamoto etc., ibid).2-methyl Third thio-acid S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] ester, and prepare and use this compound Method be described in European patent EP 1020439, Shinkai etc., J.Med.Chem.43:3566-3572 (2000) or WO 2007/051714, WO 2008/074677 or WO2011/000793.

In preferred embodiments, CETP inhibitor thioester derivant (compound of such as Formulas I or I ') is brilliant Body or the solid of amorphous form, more preferably crystal form.In specific embodiments, 2-methyl-prop thio-acid S-[2- ([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester is in crystalline form A.

A type be characterized as about 7.9 °, 8.5 °, 11.7 °, 12.7 °, 17.1 °, 18.0 °, 18.5 °, 20.2 °, 22.1 °, There is at 24.7 ° ± 0.2 ° the X-ray powder diffraction pattern at peak, be characterized as especially at 7.9 °, 11.7 °, 17.1 °, 18.5 ° The XRPD peak that the 2 θ angles of diffraction of (± 0.2 °) are observed.

Pharmaceutical composition may be used for treatment or prevention cardiovascular disorder, and it includes but not limited to: mammal, especially The atherosclerosis (atherosclerosis) of people (that is, man or woman), peripheral vascular disease (peripheral Vascular disease), dysiipidemia (dyslipidemia) (such as, hyperlipemia (hyperlipidimia)), high β Hyperlipoproteinemia (hyperbetalipoproteinemia), hypoalphalipoproteinemia (hypoalphalipoproteinemia), Hypercholesterolemia (hypercholesterolemia), hypertriglyceridemia (hypertriglyceridemia), family Property hypercholesterolemia (familial-hypercholesterolemia), angina (angina), ischemia (ischemia), Myocardial ischemia (cardiacischemia), apoplexy, myocardial infarction (myocardial infarction), reperfusion injury (reperfusion injury), angioplastic restenosis (angioplastic restenosis), hypertension, cardiovascular Disease, coronary heart disease (coronary heart disease), coronary artery disease (coronary artery disease), high fat Proteinemia (hyperlipidoproteinemia), diabetes, obesity or the blood vessel of endotoxemia (endotoxemia) Complication.

Therefore, the present invention provides treatment or the method for prevention mammal cardiovascular disorder, and described method includes to suckling The pharmaceutical composition of animal (preferably having this mammal needed) administering therapeutic effective dose.Mammal is preferably people (that is, man People or woman).People can be any race (such as, Caucasian or Asians).Cardiovascular disorder is preferably selected from by following group The group become: the atherosclerosis of mammal, peripheral vascular disease, dysiipidemia, Hyperbetalipoproteinemia, low alpha lipoprotein blood Disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, myocardial ischemia, apoplexy, Myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and the blood vessel of diabetes, obesity or endotoxemia Complication.It is highly preferred that cardiovascular disorder is selected from the group consisted of: cardiovascular diseases, coronary heart disease, coronary artery disease, low α Hyperlipoproteinemia, Hyperbetalipoproteinemia, hypercholesterolemia, hyperlipemia, atherosclerosis, hypertension, high triglyceride Mass formed by blood stasis, hyperlipoproteinemia, peripheral vascular disease, angina, ischemia and myocardial infarction.

In certain embodiments of the invention, described pharmaceutical composition comprises: 10 weight % to 69 weight %, preferably 40 Weight % is to 60 weight %, hydrophobic, the water unstable chemical combination with waxy denseness of more preferably 48 weight % to 55 weight % Thing.

In certain embodiments of the invention, described pharmaceutical composition comprises: 1 weight % to 10 weight %, preferably 5 weights Amount % to 10 weight %, the super-disintegrant of more preferably 4 weight % to 8 weight %.

In certain embodiments of the invention, described pharmaceutical composition comprises 30 weight % to 70 weight %, and preferably 30 Weight % is to 60 weight %, at least two bulk density of more preferably 40 weight % to the 50 weight % diluent less than 800g/L.

In specific embodiments, the present invention provides pharmaceutical composition, described pharmaceutical composition to comprise:

-10 weight % are to 69 weight %, and preferably 40 weight % to 60 weight %, more preferably 48 weight % are to 55 weight % There is hydrophobic, the water unstable compound of waxy denseness

-1 weight % to 10 weight %, preferably 5 weight % to 10 weight %, more preferably 4 weight % to 8 weight % super Disintegrating agent, and

-30 weight % are to 70 weight %, and preferably 30 weight % to 60 weight %, more preferably 40 weight % are to 50 weight % At least two bulk density diluent less than 800g/L.

In certain embodiments of the present invention as herein defined, described super-disintegrant is that hygroscopic polymer is composed Shape agent.Hygroscopic polymer excipient particularly as super-disintegrant is cross-linking sodium carboxymethyl cellulose.

In specific embodiments, the present invention provides compositions, described compositions to comprise:

A) 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester, and

B) cross-linking sodium carboxymethyl cellulose.

In certain embodiments of the present invention as herein defined, it is other that described compositions also comprises at least one Hygroscopic polymer excipient.

In certain embodiments of the present invention as herein defined, described compositions also comprises at least two hygroscopicity Polymeric excipient.

In certain embodiments of the present invention as herein defined, described compositions also comprises at least three kinds of hygroscopicity Polymeric excipient, two of which is the diluent that bulk density is less than 800g/L.

In certain embodiments of the present invention as herein defined, described compositions comprises 10 weight % to 69 weights 2-methyl-prop thio-acid S-[2-([[1-(2-the ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester of amount %.

In certain embodiments of the invention, described pharmaceutical composition comprises: 10 weight % to 69 weight %, preferably 40 Weight % is to 60 weight %, 2-methyl-prop thio-acid S-[2-([[1-(the 2-ethyl fourth of more preferably 48 weight % to 55 weight % Base)-cyclohexyl]-carbonyl] amino) phenyl] ester.

In certain embodiments of the present invention as herein defined, described compositions comprises 1 weight % to 10 weights Amount %, preferably 5 weight % to 10 weight %, the cross-linking sodium carboxymethyl cellulose of more preferably 5 weight % to 8 weight %.Particularly Ground, in specific embodiments, described compositions comprises the cross-linking sodium carboxymethyl cellulose of 5 weight % to 7 weight %.

In certain embodiments of the present invention as herein defined, described compositions comprises at least 30 weight %, spy Not 44 weight % are to 50 weight %, the hygroscopic polymer excipient of more particularly 46% to 48 weight %, wherein said suction Moist polymeric excipient is hydroxypropyl methyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and micronized friendship Connection polyvinylpyrrolidone.

In certain embodiments of the present invention as herein defined, described compositions comprises at least 30 weight %, excellent Select 34 weight % to 44 weight %, the hygroscopic polymer excipient of more preferably 40% to 44 weight %.

In certain embodiments of the present invention as herein defined, described compositions comprises at least 30 weight %, excellent Select the other hygroscopic polymer excipient of 34 weight % to 44 weight %, more preferably 40% to 44 weight %.

-10 weight % are to 69 weight %, and preferably 40 weight % to 60 weight %, more preferably 48 weight % are to 55 weight % 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester；

-1 weight % to 10 weight %, preferably 5 weight % to 10 weight %, the crosslinking of more preferably 4 weight % to 8 weight % Sodium carboxymethyl cellulose, and

-30% to 90 weight %, preferably 34 weight % to 44 weight %, the hygroscopicity of more preferably 40% to 44 weight % is gathered Compound excipient；

Wherein said hygroscopic polymer excipient is selected from hydroxypropyl methyl cellulose, microcrystalline Cellulose and micronized friendship Connection polyvinylpyrrolidone.

In certain embodiments of the present invention as herein defined, described compositions comprises:

A) 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl of 48 weight % to 55 weight % Base] amino) phenyl] ester；

B) cross-linking sodium carboxymethyl cellulose of 4 weight % to 8 weight %

C) the water-fast hygroscopic polymer of 32 weight % to 41 weight %；With

D) the water-soluble hygroscopic polymer of 4 weight % to 5 weight %.

In certain embodiments of the present invention as herein defined, wherein said hygroscopic polymer excipient is selected from Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxyethylmethyl-cellulose, carboxypolymethylene, Methylcellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate, polyvinylpyrrolidone, crosslinked polyethylene pyrrolidine Ketone, micronized crospolyvinylpyrrolidone, carboxymethylcellulose calcium, the carboxymethyl cellulose of crosslinking, microcrystalline Cellulose, silicon The microcrystalline Cellulose changed, cellulose powder, carboxymethyl starch, starch and pregelatinized Starch.

In certain embodiments of the present invention as herein defined, wherein said hygroscopic polymer excipient is hydroxyl Propyl methocel, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone.

In another embodiment, the present invention provides the method for preparation compositions, said method comprising the steps of:

A) by 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester, hand over Connection polyvinylpyrrolidone, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose mix and are granulated；

B) by water or in 10 weight %-30 weight % ethanol/70 weight %-90 weight % water at most up to The HPMC of 0.5 weight % is sprayed on the granule obtained according to step a)；

C) it is dried described granule；And

D) microcrystalline Cellulose, colloidal silica and sodium stearyl fumarate are mixed with the dry granule obtained according to step c) Close.

In certain embodiments of the present invention as herein defined, the two diluent is that hygroscopic polymer is composed Shape agent.Hygroscopic polymer excipient particularly as diluent is ethyl cellulose, micronized crosslinked polyethylene pyrroles Alkanone, microcrystalline Cellulose, the microcrystalline Cellulose of silication, cellulose powder, starch, pregelatinized Starch.

In certain embodiments of the present invention as herein defined, at least there are two kinds of hygroscopic polymer figurations Agent.

In certain embodiments of the present invention as herein defined, super-disintegrant and at least one diluent, or At least two diluent is hygroscopic polymer excipient.It is highly preferred that at least super-disintegrant and a kind of diluent are moisture absorptions Property polymeric excipient.

In certain embodiments of the present invention as herein defined, super-disintegrant and two kinds of diluent are hygroscopicity Polymeric excipient.

In certain embodiments of the present invention as herein defined, there are at least 30 weight %, preferably 44 weight % Hygroscopic polymer excipient to 50 weight %.

In certain embodiments of the invention, super-disintegrant is cross-linking sodium carboxymethyl cellulose.Especially, the present invention Comprise at most up to the cross-linking sodium carboxymethyl cellulose of 6 weight %.

The present invention provides the most stable pharmaceutical composition, and it comprises, and at least one is hydrophobic and water unstable gallbladder solid Alcohol ester transfer protein (CETP) inhibitor or a combination thereof, described inhibitor or a combination thereof are embedded in chemical protective hygroscopicity and gather In polymer matrix tablet, described chemical protective hygroscopic polymer substrate tablet is gathered by least one such as following hygroscopicity Compound forms: hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L- HPC), hydroxyethylmethyl-cellulose (HEMC), carboxypolymethylene (carbomer (Carbomer)), methylcellulose (MC), ethyl is fine Dimension element (EC), hydroxyethyl cellulose (HEC), cellulose acetate, polyvinylpyrrolidone (PVP), crospolyvinylpyrrolidone (crospovidone), micronized crospolyvinylpyrrolidone (micronized crospovidone), sodium carboxymethyl cellulose (crosslinking carboxylic Sodium carboxymethylcellulose pyce, CMC Na), carboxymethylcellulose calcium (cross-linked carboxymethyl cellulose calcium, CMC Ca), the carboxymethyl of crosslinking is fine Dimension element (crosslinking CMC), microcrystalline Cellulose (MCC), the microcrystalline Cellulose (MCC of silication) of silication, cellulose powder, carboxymethyl forms sediment Powder (sodium starch glycollate), starch (corn starch, potato starch, rice starch, wheaten starch, tapioca), pre-glue Changing starch or combinations thereof, its amount is preferably more than per unit 40 weight %.

The present invention provides physically stable pharmaceutical composition, and described pharmaceutical composition includes at least 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester or a combination thereof, it is embedded in chemical protective In hygroscopic polymer substrate tablet, described chemical protective hygroscopic polymer substrate tablet is by such as below at least one Hygroscopic polymer forms: hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low substituted hydroxy propyl cellulose Element (L-HPC), hydroxyethylmethyl-cellulose (HEMC), carboxypolymethylene (carbomer), methylcellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), cellulose acetate, polyvinylpyrrolidone (PVP), crospolyvinylpyrrolidone (is handed over poly- Dimension ketone), micronized crospolyvinylpyrrolidone (micronized crospovidone), sodium carboxymethyl cellulose (cross-linked carboxymethyl Sodium cellulosate, CMC Na), carboxymethylcellulose calcium (croscarmellose calcium, CMC Ca), the carboxymethyl cellulose of crosslinking (crosslinking CMC), microcrystalline Cellulose (MCC), the microcrystalline Cellulose (MCC of silication) of silication, cellulose powder, carboxymethyl starch (sodium starch glycollate), starch (corn starch, potato starch, rice starch, wheaten starch, tapioca), pregelatinated Starch or a combination thereof, its amount is preferably more than per unit 40 weight %.

Especially, the present invention provide physically stable pharmaceutical composition, described pharmaceutical composition comprise at least one dredge Water and water unstable cetp (CETP) inhibitor, described inhibitor is embedded in chemical protective hygroscopicity In polymer matrix tablet, described chemical protective hygroscopic polymer substrate tablet is by hydroxypropyl methyl cellulose, carboxymethyl Sodium cellulosate, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone composition.

Especially, the present invention provides physically stable pharmaceutical composition, described pharmaceutical composition to be embedded in 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-hexamethylene in chemical protective hygroscopic polymer substrate tablet Base]-carbonyl] amino) phenyl] ester, described chemical protective hygroscopic polymer substrate tablet is by hydroxypropyl methyl cellulose, carboxylic Sodium carboxymethylcellulose pyce, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone composition.

The present invention provides physically stable pharmaceutical composition, described pharmaceutical composition to be embedded in chemoproection 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] in property hygroscopic polymer substrate tablet Amino) phenyl] ester, described chemical protective hygroscopic polymer substrate tablet consists of: hydroxypropyl methyl cellulose, carboxylic Sodium carboxymethylcellulose pyce, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone, its amount is preferably per unit 40 weight % Above.

Generally, it is considered that make water sensitivity active pharmaceutical ingredient and substantial amounts of hygroscopic polymer such as HPMC, HPC, It is crucial that PVP, crospolyvinylpyrrolidone, CMC, crosslinking CMC with MC contact for physical stability.

Astoundingly, in the case of hydrophobic hydrolytic susceptibility CETP inhibitor, adverse effect is observed.May lead to Cross to be embedded in active substance to comprise and following hygroscopicity polymer matrix is come stabilizing active pharmaceutical ingredients and quick-release tablet two Person:

Furthermore, it was surprisingly found that, in the case of there is hydrophobic compound, the amount of hygroscopic polymer is usual from it 10 to 20 weight % increase to greater than 30 weight % and do not result in capping or the cracking of original intended quick-release tablet preparation.Cause This, when being made up of hygroscopic polymer excipient more than the tablet of 30 weight %, hydrophobic compound makes quick-release tablet avoid shape Become crackle.

In another embodiment, the present invention provides compositions, described compositions to comprise:

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %；With

B) based on composition weight, the hygroscopic polymer excipient of at least 30%, preferably 44 weight % to 50 weight %.

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %；

B) the water-fast hygroscopic polymer of 40 weight % to 45 weight %；

C) the water-soluble hygroscopic polymer of 4 weight % to 5 weight %.

In certain embodiments of the invention, at least two bulk density diluent less than 800g/L is microcrystalline Cellulose And mannitol.

In certain embodiments of the invention, at least two bulk density diluent less than 800g/L is microcrystalline Cellulose With micronized crospolyvinylpyrrolidone.

In certain embodiments of the invention, microcrystalline Cellulose and mannitol exist with the weight ratio of about 9: 1 to 1: 1.

In certain embodiments of the invention, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone are with about 5: The weight ratio of 1 to 5: 3 exists.

The CETP inhibitor thioester derivant of-48 weight % to 55 weight %；With

-at least 30 weight %, the hydroxypropyl methyl cellulose of preferably 44 weight % to 50 weight %, cross-linked carboxymethyl fiber Element sodium, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone.

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %；

B) cross-linking sodium carboxymethyl cellulose of 4 weight % to 8 weight %；With

C) hydroxypropyl methyl cellulose of 35 weight % to 44 weight %, microcrystalline Cellulose and micronized crosslinked polyethylene Ketopyrrolidine.

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %；

B) less than the micronized crospolyvinylpyrrolidone of 12 weight %；With

C) hydroxypropyl methyl cellulose of 35 weight % to 44 weight %, microcrystalline Cellulose and cross-linked carboxymethyl cellulose Sodium.

A) CETP inhibitor thioester derivant, more particularly 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl fourth Base)-cyclohexyl]-carbonyl] amino) phenyl] ester；

B) cross-linking sodium carboxymethyl cellulose.

B) microcrystalline Cellulose；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；With

E) cross-linking sodium carboxymethyl cellulose.

B) mannitol；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；

E) cross-linking sodium carboxymethyl cellulose.

B) mannitol；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；

E) cross-linking sodium carboxymethyl cellulose；

F) microcrystalline Cellulose.

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %, more particularly 2-ethyl the third thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester；

B) microcrystalline Cellulose of 24 weight % to 26 weight %；

C) the micronized crospolyvinylpyrrolidone of 11 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 4 weight % to 5 weight %；

E) cross-linking sodium carboxymethyl cellulose of 4 weight % to 6 weight %.

B) microcrystalline Cellulose of 24 weight % to 26 weight %；

C) the micronized crospolyvinylpyrrolidone of 11 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 4 weight % to 5 weight %；

E) cross-linking sodium carboxymethyl cellulose of 4 weight % to 6 weight %；

F) magnesium stearate of 0 to 1 weight %；

G) colloidal silica of 0 to 1 weight %；

H) sodium stearyl fumarate of 0 to 1 weight %.

A) the CETP inhibitor thioester derivant of 48 weight % to 55 weight %, more particularly 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester；

B) mannitol of 10 weight % to 14 weight %；

C) the micronized crospolyvinylpyrrolidone of 8 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 2 weight % to 6 weight %；

E) 5% to 9% cross-linking sodium carboxymethyl cellulose.

B) mannitol of 10 weight % to 14 weight %；

C) the micronized crospolyvinylpyrrolidone of 8 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 2 weight % to 6 weight %；

E) cross-linking sodium carboxymethyl cellulose of 5 weight % to 9 weight %；

F) microcrystalline Cellulose of 11 weight % to 15 weight %.

In certain embodiments of the invention, described compositions is pharmaceutical composition.

Pharmaceutical composition can be to be following form: pill, capsule or tablet, and its CETP each containing scheduled volume presses down Preparation thioester, and cover in particular for the situation coating swallowing (with powder or the form of granule).Especially, medicine Compositions is tablet form, and described tablet comprises CETP inhibitor thioester derivant and the tablet wherein using and describing Component.For Orally administered, fine powder or granule can contain diluent, dispersant and/or surfactant, and permissible Such as it is present in (with drying regime) in capsule or sachet, or is present in tablet, wherein can comprise binding agent and lubrication Agent.Component such as sweetener, flavoring agent, preservative, suspending agent, thickening agent and/or emulsifying agent can also be present in drug regimen In thing.

In specific embodiments, with coating based on polyvinyl alcohol (coating based on PVA), especially with below 20mg Coating based on PVA, more particularly provide film coating to compositions herein with the coating based on PVA of 15mg.

In certain embodiments of the invention, described compositions comprises the 2-methyl-prop thio-acid S-of 100mg to 600mg [2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.Especially, compositions comprises 150ng to 450mg 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.It is highly preferred that group Compound comprises the 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) of 250ng to 350mg Phenyl] ester.Most particularly, compositions comprises 2-methyl-prop thio-acid S-[2-([[1-(the 2-ethyl fourth of 250mg to 350mg Base)-cyclohexyl]-carbonyl] amino) phenyl] ester.

In another embodiment of the present invention, for paediatric use, described compositions comprises the 2-of 25mg to 300mg Methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.Especially, Peadiatric combination Thing comprises 2-methyl-prop thio-acid S-[2-([[1-(2-the ethyl-butyl)-cyclohexyl]-carbonyl] amino) benzene of 75mg to 150mg Base] ester.

CETP inhibitor can be applied to mammal with any suitable dosage (such as, reaching therapeutically effective amount).Example As, the suitable dose for the compound I of the therapeutically effective amount used to patient will be about 100mg to about 1800mg/ days.Preferable Dosage preferably about 300mg to about 900mg/ days.Preferably dosage is about 600mg/ days.

In another embodiment, the present invention provides test kit, described test kit to comprise: pharmaceutical composition, described medicine Compositions contains the CETP inhibitor thioester derivant of therapeutically effective amount and at least 30 weights based on composition weight The hygroscopic polymer excipient of amount %, the also referred to as prescription information of " loose-leaf (leaflet) ", blister package or bottle (HDPE Or glass) and container.Prescription information preferably include to patient about following suggestion: CETP inhibitor thioester is derived The compound of thing (such as formula (I ')) use together with food, especially for the life improving CETP inhibitor thioester derivant Thing availability.

In another embodiment, the present invention provides test kit, described test kit to comprise compositions as described herein, The also referred to as prescription information of " loose-leaf ", blister package or bottle (HDPE or glass) and container.Described prescription information preferably includes To patient about following suggestion: use CETP inhibitor thioester derivant (such as formula (I ') together with food Compound), especially for the bioavailability improving CETP inhibitor thioester derivant.

In another embodiment, the present invention provides test kit, described test kit to comprise: compositions, described compositions 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] containing therapeutically effective amount Ester and the hygroscopic polymer excipient of based on composition weight at least 30 weight %, prescription information, blister package or bottle and appearance Device.In specific embodiments, the present invention provides test kit as described herein, wherein said prescription information to include to patient's Suggestion about following: together with food use 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]- Carbonyl] amino) phenyl] ester.

In another embodiment, the present invention provides the tablet comprising compositions as described herein.

In another embodiment, the present invention provides compositions as described herein, its for preparation for treatment or Prevention cardiovascular disorder medicine, especially, wherein 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]- Carbonyl] amino) phenyl] ester is with 100mg to 1800mg, and the daily dose of 300mg to 900mg especially, more particularly 600mg is executed With, wherein 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester Use together with food.In another embodiment, the present invention provides the method preparing compositions as described herein, described Method comprises the following steps:

A) will have the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, crystallite is fine Dimension element, cross-linking sodium carboxymethyl cellulose and optional hydroxypropyl methyl cellulose mix and are granulated；

B) will be in water or at 10 weight %-30 weight % ethanol/70 weight %-90 weight % water (more particularly 20 weights Amount % ethanol/80 weight % water) at most up to the hydroxypropyl methyl cellulose of 0.5 weight %, be sprayed on and obtain according to step a) On the granule obtained；

C) it is dried described granule；And

In another embodiment, the present invention provides the method preparing compositions as herein described, described method to include Following steps:

A) will have the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, mannitol, Cross-linking sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose mix and are granulated；

C) it is dried described granule；And

A) will have the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, crystallite is fine Dimension element and cross-linking sodium carboxymethyl cellulose mix and are granulated；

B) by 10 weight %-30 weight % ethanol/70 weight %-90 weight % water, more particularly at 20 weights Hydroxypropyl methyl cellulose in amount % ethanol/80 weight % water, is sprayed on the granule obtained according to step a)；

C) it is dried described granule；And

A) will have the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, crystallite is fine Dimension element, cross-linking sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose mix and are granulated；

B) will be made up of 10 weight %-30 weight % ethanol/70 weight %-90 weight % water, more particularly by 20 weights The granulation liquid (granulation fluid) of amount % ethanol/80 weight % water composition, is sprayed on the granule obtained according to step a) On；

C) it is dried described granule；

D) by microcrystalline Cellulose, colloidal silica and sodium stearyl fumarate mix with the dry granule obtained according to step c) Close；

E) tabletting；

F) with the air intake of≤60 DEG C, tablet is preheated until reaching the tablet temperature of about 43 DEG C；

G) by coating suspensionsIt is sprayed on tablet；And

H) in porose coating pan (coating pan) persistently rotate under dry film coated tablet.

Preparation method:

In this article, API refers to such active substance, and it is hydrophobic, the water unstable chemical combination with waxy denseness Thing, particularly relates to CETP inhibitor thioester derivant, more particularly refers to the CETP inhibitor thio-acid of formula (I) or (I ') Ester derivant.In embodiment 1 to 45, API refer to the formula (I ') of crystal form thio isobutyrate S-(2-{ [1-(2-ethyl- Butyl)-cyclohexane carbo]-amino }-phenyl) ester.

The compositions of the present invention can be prepared according to any known method, and described method causes being substantially maintained as API Crystal form (amount of the hydrophobic API of amorphous form is less than 10 weight %).Additionally, the compositions of the present invention can be according to appointing Prepared by what known method, described method causes that API is substantially maintained as crystal form, and (essentially amorphous form has wax The amount hydrophobic, water unstable compound of sample denseness is less than 10 weight %).

Preparation may comprise steps of according to the method for the pharmaceutical composition of the present invention:

1) under continuous stirring hydroxypropyl methyl cellulose (total hydroxypropyl methyl cellulose of 0.5 weight %) is dissolved in In 20 weight % ethanol and 80 weight % water；

2) will have hydrophobic, the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, micro- Crystalline cellulose, cross-linking sodium carboxymethyl cellulose and remaining hydroxypropyl methyl cellulose are loaded onto the system with bottom driving impeller Grain machine (high shear mixer: such as) vertical granulator；

3) impeller and the grain fraction of chipper combination drying are used；

4) under the lasting mixing using impeller and chipper, granule is made to moisten by spray granulation liquid；

5) impeller and chipper is used to mediate moistening granule；

6) wet granular is discharged, at taper grinding machine (conical mill) [such as(there is the sieve of rotary blade Mill)) on it is sieved；Filter with the square sieve of 10mm (square screen) and be then fed in fluidized bed dryer

7) at fluidized bed dryer (such asIn), utilize the intake air temperature of≤60 DEG C be dried granule until reach≤ The final LOD (loss on drying) of 3.5 weight %；

8) discharge the granule being dried, and use the impact grinder (impact mill) being furnished with 1.5mm circular perforations sieve (such asIt is ground by (having the impact grinder of rotary hammer)；

9) on the sieve being furnished with 1mm circular perforations sieve, component (the such as microcrystalline Cellulose, colloidal state of foreign minister is added to granule Silicon dioxide and sodium stearyl fumarate)

10) by all components at performance chamber mixer (bin blender) (such as(at performance chamber mixer Middle bucket mixes)) middle mixing；

11) with low compression stress (about 6kN) at rotary tablet machine (such asTabletting is carried out in (power-assisted)；

12) pass through under continuous stirring toComplete coated systems (complete coating System) it is suspended in water and prepares coating suspensions；

13) tablet is fed in porose coating pan；

14) at porose coating pan (such as(porose coated systems)) lasting rotation under, utilize≤60 DEG C Air inlet by tablet preheating until reaching the tablet temperature of about 43 DEG C；

15) under the lasting rotation of porose coating pan, coating suspensions is sprayed on tablet；

16) in porose coating pan, under lasting rotation, dry film coated tablet；

17) film coating tablet is discharged.

Alternatively, such as having the compositions of hydroxypropyl methyl cellulose 6cp, prepare the medicine group according to the present invention The method of compound may comprise steps of:

1) under continuous stirring all hydroxypropyl methyl celluloses are dissolved in 20 weight % ethanol and 80 weight % water；

2) will have hydrophobic, the water unstable compound of waxy denseness, micronized crospolyvinylpyrrolidone, micro- Crystalline cellulose, cross-linking sodium carboxymethyl cellulose is loaded into the granulator (high shear mixer: such as with bottom driving impeller) vertical granulator；

3) impeller and the grain fraction of chipper combination drying are used；

5) impeller and chipper is used to mediate moistening granule；

6) wet granular is discharged, at taper grinding machine (such as(there is the screen mill of rotary blade)) on it is carried out Screening；With the square sieved filter of 10mm and be then fed in fluidized bed dryer

8) discharge the granule being dried, and use is furnished with the impact grinder of 1.5mm circular perforations sieve (such as It is ground by (having the impact grinder of rotary hammer)；

10) by all components at performance chamber mixer (such as(in performance chamber mixer bucket mix)) in mixed Close；

12) pass through under continuous stirring toCoated systems completely is suspended in water and prepares coating suspensions；

13) tablet is fed in porose coating pan；

16) in porose coating pan, under lasting rotation, dry film coated tablet；

17) film coating tablet is discharged.

From following example, other features of the present invention and embodiment will be apparent from, and provide following example and are Illustrate the invention without the scope limiting its anticipation.

Embodiment 1 to 42 and placebo embodiment A are prepared according to above-mentioned conventional method, and wherein for embodiment A, API is Through being replaced by mannitol.Embodiment 1 to 42 all uses 20mg coating based on PVA (such as) carry out film coating.

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Embodiment B:

The two kinds of tablet sections will prepared according to embodiment 1 and embodiment A, and collect their radioscopic image.Two width figures All represent the coverage diagram (overlayed) of all X-ray section for rebuilding 3D tablet produced during measuring.Fig. 1 is not Showing that any defect only shows smooth surface, Fig. 2 has a lot of crackle.These crackles can also pass through human eye detection.

Embodiment C:

Utilize STOE STADI P diffractometer (Cu K α radiation source, main monochromator (primary monochromator), position Put sensitive detector, 2 θ of angular range 3 ° to 42 °, the overall measurement time of about 60 minutes), in environmental condition, at transmission geometry Learn in (transmission geometry), record 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl Base] amino) phenyl] the XRPD pattern of crystalline esters A type.Prepare and analyze sample, and this material is not further processed (such as mill or sieve).

Claims

1. a compositions, described compositions comprises:

B) cross-linking sodium carboxymethyl cellulose.

Compositions the most according to claim 1, described compositions also comprises at least one other hygroscopic polymer and composes Shape agent.

Compositions the most according to claim 1, described compositions also comprises the other hygroscopic polymer of at least two and composes Shape agent.

Compositions the most according to claim 1, described compositions also comprises at least three kinds of other hygroscopic polymers and composes Shape agent, two of which is the diluent that bulk density is less than 800g/L.

Compositions the most according to any one of claim 1 to 4, described compositions comprises 10 weight % to 69 weight % 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.

Compositions the most according to any one of claim 1 to 5, described compositions comprises 40 weight % to 60 weight % 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.

Compositions the most according to any one of claim 1 to 6, described compositions comprises 48 weight % to 55 weight % 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.

Compositions the most according to any one of claim 1 to 7, described compositions comprises 1 weight % to 10 weight % Cross-linking sodium carboxymethyl cellulose.

Compositions the most according to any one of claim 1 to 8, described compositions comprises 5 weight % to 10 weight % Cross-linking sodium carboxymethyl cellulose.

Compositions the most according to any one of claim 1 to 9, described compositions comprises 5 weight % to 8 weight % Cross-linking sodium carboxymethyl cellulose.

11. compositionss according to any one of claim 1 to 10, described compositions comprises 5 weight % to 7 weight % Cross-linking sodium carboxymethyl cellulose.

12. according to the compositions according to any one of claim 1 to 11, and described compositions comprises 30 weight % to 70 weight % At least two bulk density less than the diluent of 800g/L.

13. according to the compositions according to any one of claim 1 to 12, and described compositions comprises 30 weight % to 60 weight % At least two bulk density less than the diluent of 800g/L.

14. according to the compositions according to any one of claim 1 to 13, and described compositions comprises 40 weight % to 50 weight % At least two bulk density less than the diluent of 800g/L.

15., according to the compositions according to any one of claim 1 to 11, wherein exist the described hygroscopicity of at least 30 weight % Polymeric excipient.

16. according to the compositions according to any one of claim 2 to 11 or 15, wherein there are 34 weight % to 44 weight % Described other hygroscopic polymer excipient.

17., according to claim 2 to 11, compositions according to any one of 15 or 16, wherein exist 40 weight % to 44 weights The described other hygroscopic polymer excipient of amount %.

18. according to the compositions according to any one of claim 2 to 17, and wherein said hygroscopic polymer excipient is so Polymeric excipient, it is by even under the relative humidity of as little as 50%, at room temperature absorption or absorb moisture.

19. compositionss according to any one of claim 1 to 3, described compositions comprises:

A) more than 2-methyl-prop thio-acid S-[2-([[1-(2-the ethyl-butyl)-cyclohexyl]-carbonyl] amino) benzene of 50 weight % Base] ester；

B) more than the water-fast hygroscopic polymer of 40 weight %；

C) more than the water-soluble hygroscopic polymer of 4 weight %；With

D) other excipient less than 6%.

20. comprise according to the compositions according to any one of claim 1 to 18, described compositions:

A) the 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] of 48 weight % to 55 weight % Amino) phenyl] ester；

B) cross-linking sodium carboxymethyl cellulose of 4 weight % to 8 weight %；

C) the water-fast hygroscopic polymer of 32 weight % to 41 weight %；With

D) the water-soluble hygroscopic polymer of 4 weight % to 5 weight %.

21. are selected from hydroxyl according to the compositions according to any one of claim 2 to 20, wherein said hygroscopic polymer excipient Propyl methocel, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxyethylmethyl-cellulose, carboxypolymethylene, first Base cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate, polyvinylpyrrolidone, crosslinked polyethylene pyrrolidine Ketone, micronized crospolyvinylpyrrolidone, carboxymethylcellulose calcium, the carboxymethyl cellulose of crosslinking, microcrystalline Cellulose, silicon The microcrystalline Cellulose of change, cellulose powder, carboxymethyl starch, starch, pregelatinized Starch.

22. according to the compositions according to any one of claim 2 to 21, and wherein said hygroscopic polymer excipient is hydroxypropyl Ylmethyl cellulose, microcrystalline Cellulose and micronized crospolyvinylpyrrolidone.

23. comprise according to the compositions according to any one of claim 1 to 22, described compositions:

A) 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester；

B) microcrystalline Cellulose；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；With

E) cross-linking sodium carboxymethyl cellulose.

24. compositionss according to any one of claim 1 to 3, described compositions comprises:

A) CETP inhibitor thioester (thhiosester) derivant of 48 weight % to 55 weight %；With

B) hydroxypropyl methyl cellulose of at least 30 weight %, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and micronized Crospolyvinylpyrrolidone.

25. comprise according to the compositions according to any one of claim 1 to 24, described compositions:

A) CETP inhibitor thioester derivant, more particularly 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)- Cyclohexyl]-carbonyl] amino) phenyl] ester；

B) mannitol；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；

E) cross-linking sodium carboxymethyl cellulose；

F) microcrystalline Cellulose.

26. comprise according to the compositions according to any one of claim 1 to 23, described compositions:

C) hydroxypropyl methyl cellulose of 35 weight % to 44 weight %, microcrystalline Cellulose and micronized crosslinked polyethylene pyrroles Alkanone.

27. comprise according to the compositions according to any one of claim 1 to 23 or 26, described compositions:

B) microcrystalline Cellulose of 24 weight % to 26 weight %；

C) the micronized crospolyvinylpyrrolidone of 11 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 4 weight % to 5 weight %；

E) cross-linking sodium carboxymethyl cellulose of 4 weight % to 6 weight %.

28. according to claim 1 to 23, compositions according to any one of 26 or 27, and described compositions comprises:

B) microcrystalline Cellulose of 24 weight % to 26 weight %；

C) the micronized crospolyvinylpyrrolidone of 11 weight % to 12 weight %；

D) hydroxypropyl methyl cellulose of 4 weight % to 5 weight %；

E) cross-linking sodium carboxymethyl cellulose of 4 weight % to 6 weight %；

F) magnesium stearate of 0 to 1 weight %；

G) colloidal silica of 0 to 1 weight %；

H) sodium stearyl fumarate of 0 to 1 weight %.

29. according to the compositions according to any one of claim 1 to 14, and two kinds of bulk densities of at least a part of which are dilute less than 800g/L's Releasing agent is microcrystalline Cellulose and mannitol.

30. according to the compositions according to any one of claim 1 to 14, and two kinds of bulk densities of at least a part of which are dilute less than 800g/L's Releasing agent is microcrystalline Cellulose and micronized crospolyvinylpyrrolidone.

31. is tablet form according to the compositions according to any one of claims 1 to 30, wherein said compositions.

32. according to the compositions according to any one of claims 1 to 31, wherein 2-methyl-prop thio-acid S-[2-([[1-(2- Ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester is crystal form.

33. according to the compositions according to any one of claims 1 to 32, and it is used for treating or preventing cardiovascular disorder.

34. according to the compositions according to any one of claims 1 to 32, and it is for treating or prevent the use of cardiovascular disorder On the way.

35. is Atherosclerosis according to the compositions according to any one of claim 33 or 34, wherein said cardiovascular disorder Change, peripheral vascular disease, dysiipidemia (such as, hyperlipemia), Hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia Mass formed by blood stasis, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, myocardial ischemia, apoplexy, myocardial infarction, then Perfusion injury, angioplastic restenosis, hypertension, cardiovascular diseases, coronary heart disease, coronary artery disease, hyperlipoproteinemia, sugar Urine disease, obesity or the vascular complication of endotoxemia.

36. 1 kinds of tablets comprised according to the compositions according to any one of claims 1 to 32.

37. are used for treating or preventing cardiovascular disorder in preparation according to the compositions according to any one of claims 1 to 32 Purposes in medicine.

38. is atherosclerosis according to the purposes described in claim 37, wherein said cardiovascular disorder, peripheral vascular disease, Dysiipidemia (such as, hyperlipemia), Hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, high triglyceride Mass formed by blood stasis, familial hypercholesterolemia, angina, ischemia, myocardial ischemia, apoplexy, myocardial infarction, reperfusion injury, blood vessel becomes Shape art restenosis, hypertension, cardiovascular diseases, coronary heart disease, coronary artery disease, hyperlipoproteinemia, diabetes, obesity or interior The vascular complication of Endotoxemia.

39. according to the purposes described in claim 38, wherein 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-hexamethylene Base]-carbonyl] amino) phenyl] ester is with the daily dose of 100mg to 1800mg, especially 300mg to 900mg, more particularly 600mg Use.

40. according to the purposes described in claim 38 or 39, wherein 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)- Cyclohexyl]-carbonyl] amino) phenyl] ester uses together with food.

41. 1 kinds of methods preparing compositions, said method comprising the steps of:

A) by 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester, micronization Crospolyvinylpyrrolidone, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose mixing and grain Change；

B) by water or in 10 weight %-30 weight % ethanol/70 weight %-90 weight % water at most up to 0.5 weight The hydroxypropyl methyl cellulose of amount % is sprayed on the granule obtained according to step a)；

C) it is dried described granule；And

D) microcrystalline Cellulose, colloidal silica and sodium stearyl fumarate are mixed with the dry granule obtained according to step c).

42. 1 kinds of test kits, described test kit comprises: compositions, and described compositions contains the 2-methyl rosickyite of therapeutically effective amount Generation acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester and at least 30 weight based on composition weight The hygroscopic polymer excipient of amount %；Prescription information；Blister package or bottle and container.

43. test kits according to claim 42, wherein said prescription information include to patient about together with food one Act the suggestion using 2-methyl-prop thio-acid S-[2-([[1-(2-ethyl-butyl)-cyclohexyl]-carbonyl] amino) phenyl] ester.

44. comprise according to the test kit described in claim 42 or 43, wherein said compositions:

B) microcrystalline Cellulose；

C) micronized crospolyvinylpyrrolidone；

D) hydroxypropyl methyl cellulose；With

E) cross-linking sodium carboxymethyl cellulose.

45. inventions as discussed herein above.